RNA Editing Emerging as a Broadly Applicable Oligonucleotide Therapeutics Modality

This feels like RNAi all over again. 20 Years after my life-altering journey in RNAi Therapeutics started, I can’t shake a similar sensation for the almost boundless therapeutic opportunities around RNA Editing.

RNA Editing in our context refers to the directed change from Adenine (A) to Inosine (I) in an RNA molecule with ‘I’ being read as a ‘G’ by the molecular machineries inside a cell.  This process harnesses endogenous ADAR enzymes (Adenine Deaminases Acting on RNA) which recognize certain double-stranded RNA features upon which nearby ‘A’s are converted to ‘I’s.  These recruiting features can be created in a sequence-directed manner through the interaction of exogenously applied oligonucleotides with complementarity to cellular target RNA, typically mRNA.

Other types of RNA editing, for example ‘C’ to ‘U’ are also being explored, but as a readily sequence adaptable platform, ‘A’ to ‘I’ excites me the most right now and appears ready for prime time.

 

Boundless therapeutic opportunities

When I was first pitched with the concept of RNA Editing, I was skeptical.  I merely saw it as a gene therapy alternative for ultra orphan applications aiming to revert pathogenic ‘A’s into wildtype or less pathogenic ‘G’s. 

Even fairly common genetic diseases like Duchenne muscular dystrophy and cystic fibrosis for example can be caused by hundreds of different point mutations and it would seem overly cumbersome to develop different oligos to address unique mutations of individual patients.

Also, how would it compete here with genome editing technologies like CRISPR that aim for one-time treatments to achieve the same?

It was during a recent trip back to Stanford when I voiced such concerns as Billy Li remarked in passing that RNA Editing was not limited to such genetic therapies in the traditional sense, but could also be used more widely to modulate wildtype mRNAs to influence processes such as signaling pathways for diseases involving much larger target populations.

Billy Li is an associate professor at Stanford University and a leading researcher on ADAR molecular biology and genetics.

To influence signaling pathways, you may for example target RNA Editing to abolish phosphorylation sites or other amino acids critical for protein-protein interaction.  Often, this will have gain-of-function effects such that editing only a fraction of the target RNAs may result in dramatic upregulation of a pathway.

Tunability and temporary modulation as opposed to the binary nature of genome editing is another attraction of RNA Editing.  You can easily see for example that having a signaling pathway permanently fully switched ON could pose a safety issue.

In addition to changing the coding potential of a target mRNA, RNA Editing can also be used for altering RNA processing sites, especially those regulating splicing, RNA stability and transport.

 

Ready to shine

While it has taken RNAi Therapeutics roughly 15 years from the early start-up phase to having its first drug approved for clinical use, the timeline for realizing the therapeutic potential of RNA Editing should be shortened. 

In particular, much has been learned about the delivery of oligonucleotides such that related oligonucleotide stabilization and conjugation chemistries can be rapidly translated to RNA Editing.  First clinical trials will likely be for applications in the liver and CNS, followed by the eye and lung.   

Similarly, the modification toolbox and the dramatically lowered cost of large-scale oligo synthesis and screening can be exploited to improve targeting specificity and to identify highly active RNA Editing oligos.

   

Investment opportunities

I get my adrenaline kick when science and the stock market come together.  After seeing RNAi Therapeutics mature into a widely accepted therapeutic modality, I had increasingly turned my stock market trading to biotech in general.  While this allowed me to learn much about the regulatory and late-stage aspects of drug development and marketing, I have come to miss the passion I felt while diving into the molecular biology and competitive dynamics of RNAi as it was still developing.

I know many of you are biotech investors and feel the same.  So while RNA Editing investment opportunities are not limited to the stock market, this blog will shine particular light on publicly traded biotechs in the field. 

For full disclosure, I have started a position in ProQR (ticker: PRQR; market cap: $62M), to my knowledge the only public pure-play RNA Editing biotech.  After a failed trial involving antisense oligo-mediated splice modulation it now trades at ~50% below cash suggesting that all that was left is an empty biotech shell.  It couldn't be further from the truth as ProQRians have been working on RNA Editing for almost a decade and now find themselves leading the charge of a hot new biotech platform.  Along the way, ProQR has been working on potentially critical IP and it is also for this reason that Eli Lilly has partnered with it on up to 5 RNA editing programs.  ProQR has been in a quiet period.  The next catalyst will be the announcement of more concrete development timelines and programs.  While we are waiting, the projected 2026 cash runway and partnering potential provides the company and investors with a nice cushion in these turbulent times.

Wave Life Sciences (ticker WVE; market cap: $320M) may be first into the clinic with alpha-1-antitrypsin, but as a most diverse oligonucleotide therapeutics company it is burning through its cash much more rapidly, spending it on less promising antisense knockdown and exon skipping programs.  For RNA Editing, I like it for their deep expertise in oligonucleotide chemistry and their editing efficiencies appear leading.

Stoke Therapeutics (ticker STOK; market cap $520M) is another ticker to watch as it uses oligonucleotides in more general for gain-of-function purposes.